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Published on: January 10, 2015
Cigarette smoke inhibits ROCK2 activation in T cells and modulates IL-22 production
Chien-Huan Weng1, Sanjay Gupta2, Patrick Geraghty3
1Graduate Program in Biochemistry, Cell and Molecular Biology, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA; Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021, USA.
Abstract:
Gene-environment interactions are known to play a key role in the development of rheumatoid arthritis (RA). Exposure to cigarette smoke (CS) is one of the strongest environmental risk factors associated with RA and has been shown to mediate a range of complex immunomodulatory effects from decreased T and B cell activation to depressed phagocytic function. The effects of CS on the function of TH17 cells, one of the key TH effector subsets implicated in RA pathogenesis, are not fully understood. IRF4 is one of the crucial transcription factors involved in TH-17 differentiation and is absolutely required for the production of IL-17 and IL-21 but, interestingly, inhibits the synthesis of IL-22. The production of IL-17 and IL-21 by IRF4 can be augmented by its phosphorylation by the serine-threonine kinase ROCK2. Given that CS has been reported to increase ROCK activity in endothelial cells, here we investigated the effects of CS on the ROCK2-IRF4 axis in T cells. Surprisingly, we found that CS leads to decreased ROCK2 activation and IRF4 phosphorylation in T cells. This effect was associated with increased IL-22 production. Using a GEF pull-down assay we furthermore identify ARHGEF1 as a key upstream regulator of ROCK2 whose activity in T cells is inhibited by CS. Thus CS can inhibit the ROCK2-IRF4 axis and modulate T cell production of IL-22.
Insights
Cigarette smoke (CS) alters T cell function, decreasing ROCK2-IRF4 signaling. This surprising finding in rheumatoid arthritis research reveals CS increases IL-22 production by inhibiting T cell activation pathways.
Area of Science:
- Immunology
- Molecular Biology
Background:
- Rheumatoid arthritis (RA) pathogenesis involves complex gene-environment interactions.
- Cigarette smoke (CS) is a significant environmental risk factor for RA, impacting immune cell function.
- The specific effects of CS on T helper 17 (TH17) cells, crucial in RA, remain unclear.
Purpose of the Study:
- To investigate the impact of CS on the ROCK2-IRF4 signaling axis in T cells.
- To determine how CS affects the production of cytokines IL-17, IL-21, and IL-22 by T cells.
- To identify upstream regulators of ROCK2 influenced by CS exposure.
Main Methods:
- Analysis of ROCK2 activation and IRF4 phosphorylation in T cells exposed to CS.
- Measurement of IL-17, IL-21, and IL-22 production.
- GEF pull-down assays to identify ROCK2 regulators.
Main Results:
- CS exposure led to decreased ROCK2 activation and IRF4 phosphorylation in T cells.
- This inhibition was associated with an unexpected increase in IL-22 production.
- ARHGEF1 was identified as an upstream regulator of ROCK2, with its activity inhibited by CS.
Conclusions:
- CS inhibits the ROCK2-IRF4 signaling pathway in T cells.
- CS exposure modulates T cell cytokine production, specifically increasing IL-22.
- These findings provide new insights into the immunomodulatory effects of CS in the context of RA.
